The broad long term goal of this project is to define the molecular mechanism(s) by which p62(dok) exerts its effect(s) on p210bcr-abl-mediated transformation and cell proliferation in general, and to obtain a better understanding of the establishment of the myeloproliferative phenotype of p210 bcr-abl in CML at a molecular level. p62(dok) is a protein identified as being constitutively tyrosine phosphorylated in chronic phase progenitor cells of CML patients and has been found to be a common substrate of many receptor and membrane-associated tyrosine kinases. Several lines of evidence indicate that p62(dok) plays a negative role in growth factor-induced cell proliferation, and in p210bcr-abl mediated transformation. An intriguing possibility is that p62(dok) could influence the establishment or duration of the chronic phase of CML. In light of this, the characterization of the mechanism(s) by which p62(dok) exerts its effect on growth factor and p210bcr-abl-mediated signaling is essential, as is comprehensive knowledge of bcr-abl-induced signaling pathways, and aberrations therein. To this end, we propose the following specific aims: 1) To map and compare the sites of p62(dok) tyrosine phosphorylated by p210 bcr-abl with those phoshorylated upon PDGF stimulation, 2) To define mechanisms by which p62(dok) [suppresses PDGF-triggered proliferation and p210bcr-abl-nduced transformation, 3) To identify and characterize p62(dok)-interacting signaling components which mediate the negative effect of p62(dok) on PDGF-triggered proliferation and p210bcr-abl-induced transformation, 4) To define signal transduction pathways affected by p210 bcr-abl by microarray analysis and clustering resulting data, and 5) To characterize the target genes involved in the p210 bcr-abl signal transduction pathways identified. This project offers biochemical, molecular and cellular approaches to the study of p62(dok) with respect to its involvement in CML and to the identification of bcr-abl target genes. The health-relatedness of this project is that defining the role of p62(dok) in p210 bcr-abl signaling, and the identification of novel target genes of bcr-abl, will contribute to a better understanding of the establishment of human CML. Furthermore the identification of novel target genes of p210 bcr-abl signaling may provide new potential targets for therapeutic intervention.